Although hepatitis C virus (HCV) is a leading cause of morbidity and mortality worldwide, the role of viral cytopathic effects remains unclear. To study the biosynthesis of HCV structural proteins and their pathogenic role, transgenic mice expressing type 1b HCV structural proteins (core, E1 and E2) have been constructed using liver-specific promoters. Expression of HCV transgenes was detected in several lines by Northern blot, HCV-specific reverse transcriptase-polymerase chain reaction (RT-PCR), and Western immunoblotting. Immunohistochemical analysis revealed a predominately cytoplasmic presence of core protein with occasional nuclear staining, and both cytoplasmic and membrane expression of the E2 protein in the transgenic livers. At six months of age, the livers of all transgenic lineages remain histologically normal. Therefore HCV structural proteins are not directly cytopathic in this animal model. Our laboratory are also generating transgenic mice with full-length HCV genome and are developing a system for inducible expression of HCV transgenes using the tetracycline-inducible system. These animal will provide a useful animal model not only to address issues of immunopathogenesis and cytopathic potential of HCV gene products but also to study HCV replication in vivo.